Arsenic (As) carcinogenesis is a unique example of discrepancy between positive human findings and negative animal tests. Two hypotheses are investigated in an attempt to clear this discrepancy: (a) species-specific differences of As metabolism between humans and laboratory rodents used in carcinogenesis tests; (b) requirements for combined exposures with other agents in co-carcinogenic interactions. It was found that the mouse is able to methylate inorganic arsenic in vivo; this biotransformation is similar to that in humans and considerably more effective than that occurring in the rat. In vitro culture models were selected in which to investigate arsenic metabolism and its interaction with other compounds. Transformation and toxicity studies were conducted using the mouse embryo cell line BALB/3T3 clone A31-1-1. In this system, trivalent As was found to have higher toxicity than pentavalent As; transformed foci were induced by trivalent As while pentavalent As was negative. Primary mouse epidermal cell cultures are also used. The conditions needed for arsenic methylation and the effect of arsenic on epidermal cell differentiation and keratin synthesis in culture are studied. Growth conditions were successfully established for these cultures by replacing serum with four defined factors in low calcium basal medium. Primary hamster epidermal cell and bronchial epithelial cell culture systems are considered for future use. In vivo carcinogenesis protocols are developed according to the information obtained from in vivo and in vitro metabolic studies and from studies of target cells in culture.